Estimates from the World Health Organization indicate there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. Diabetes mellitus is a metabolic disorder characterized by hyperglycemia and is associated with abnormalities in carbohydrate, fat and protein metabolism resulting in chronic complications including microvascular, macrovascular and neuropathic problems (Oki et al, 2002). Type 2 diabetes is associated with a number of cardiovascular risks including dyslipidemia and hypertension. It is the leading cause of end-stage renal disease (ESDR) which manifests as disturbances in the ability of the kidneys to handle sodium. The thiazolidinediones (TZDs) have been introduced for the treatment of type 2 diabetes. These agents are ligands for peroxisome proliferator activated gamma receptors (PPAR3) and are used in type 2 diabetes since they work by reducing glucose level through decreasing insulin resistance. In our previous study, we defined a role for PPAR1 in sodium handling by the kidney and our results showed that deletion of PPAR1 gene caused a defective Na-Cl cotransporter (NCC) activity as evidenced by a reduced hydrochlorothiazide-sensitive sodium excretion. Based on these observations, we hypothesized that sodium handling is impaired in type 2 diabetes and that PPAR1 gene offers protection from the sodium impairment. Because PPAR3 and PPAR1 share the same peroxisome response elements and can be transactivated by the same ligands, we hypothesize therefore, that PPAR3 will play a defined role in sodium handling in type 2 diabetes. To achieve this goal, we will be using db/db mice and PPAR ligand, pioglitazone to dissect the involvement of PPAR3 in sodium handling in type 2 diabetes. In the first set of experiments, the diabetic, db/db -/- mice will be challenged with a sodium load in diet and the extent of sodium excretion will be evaluated. In another set of experiments, we will examine the role of pioglitazone in in vivo natriuretic mechanisms in type 2 diabetes by evaluating the differential sensitivity of ion transporters in the nephron to hydrochlorothiazide, amiloride, or furosemide, as indices of activity of sodium chloride co-transporter (NCC), sodium hydrogen exchanger (NHE) and sodium-potassium chloride cotransporter (NKCC), respectively. This study meets Xavier University's institutional goal to eliminate health disparity. This pilot study will contribute significantly to knowledge and provide further insights into the molecular and cellular underpinnings of impaired sodium handling in diabetes. The information obtained from this study will enable the Principal Investigator to apply for competitive external grants like R01 in the future.